Percutaneous absorption-type pharmaceutical preparations have many advantages in that they may evade drug absorption by digestive tubes and may evade initial drug passing through liver, that they are applicable even to persons for whom oral drug administration is difficult and that they may be effective for preventing forgetful drug administration, and recently, they have become much highlighted as excellent drug administration modes because of such their various advantages, and various types of percutaneous absorption-type pharmaceutical preparations have been developed.
Recently, some new functions have become imparted to some percutaneous absorption-type pharmaceutical preparations, for example, types of diseases (e.g., cardiopathy, etc.) applicable to percutaneous absorption-type pharmaceutical preparations are printed on the covers of the preparations, and even when patients have become under unconsciousness, erroneous drug administration (contraindicant drug administration) to them could be evaded, and further development of those percutaneous absorption-type pharmaceutical preparations in future is expected.
However, when asked as to whether any and every drug could be usable for percutaneous administration, in fact, it must be said that most drugs are unsuitable to percutaneous administration. There are many drugs in the form of their acidic salts such as hydrochlorides, but when such acidic salts are, as they are, directly formulated into percutaneous absorption-type pharmaceutical preparations, then their hydrophilic properties derived from salts may have a significant influence on the preparations. As a result, there are many cases where the drugs in the resultant preparations could hardly penetrate through a keratin layer that is in a hydrophilic environment, and therefore the preparations could not bring about a necessary drug concentration in blood. Regarding this, many techniques of converting acidic salt drugs in preparations into free-form drugs by the use of basic compounds (neutralization) have been investigated. In general, organic amines are utilized for the basic compounds in such techniques, but amino group-having polymer compounds are also utilized for them. Organic amines may be effective for neutralization, but they are relatively unstable by themselves and their purification is difficult. Therefore, they are problematic in that their purity is low and they may color drugs or may often decompose drugs. On the other hand, regarding amino group-having polymer compounds, their amount necessary for neutralization of drugs is larger than that of low-molecular compounds of organic amines, or that is, a larger amount of such a polymer compound must be added for the necessary neutralization. Another problem with them is that such polymer compounds could not have good adhesiveness, and therefore when they are added to percutaneous absorption-type pharmaceutical preparations, then they may lower the adhesiveness of the preparations. The adhesiveness thereof is the second important factor of percutaneous absorption-type pharmaceutical preparations, next to the most important factor thereof of drug permeability. In case where the adhesiveness of a percutaneous absorption-type pharmaceutical preparation applied to a minor disease is poor and where the preparation is readily stripped away because of the poor adhesiveness, then it would be unexpected that the patient's disease might be soon worse. However, when the same has occurred in a patient suffering from a serious disease, then it would soon result in a serious problem.
Regarding drug administration for diseases, the administration period is preferably shorter, but in real life, drugs are often administered for a long period of time. In case where a percutaneous absorption-type pharmaceutical preparation is applied during such a long-term administration period, then the administration shall be repeated almost everyday. Recently, 3-days lasting preparations and 1-week lasting preparations are being developed for practical use. The site to which a percutaneous absorption-type pharmaceutical preparation is applied is preferably one except the moving sites of a body especially for preventing the problem of stripping, and it is understood that percutaneous absorption-type pharmaceutical preparations are limited in point of the applicable site thereof. Regarding their types, various types such as reservoir-type or matrix-type of percutaneous absorption-type pharmaceutical preparations are known. However, they could not still solve the problem of their applicability to limited sites. In addition, the influence of users' feeling in application and especially stripping of those percutaneous absorption-type pharmaceutical preparations on the users' bodies is significantly great.
On the assumption of repeated application thereof from the above, percutaneous absorption-type pharmaceutical preparations are required to be as soft as possible to the skin so as not to irritate the skin surface to cause keratin damage, or that is, the preparations are desired to be less irritative. Regarding it, there may be mentioned a method of changing the composition of the adhesive itself to be employed so as to suitably lower the adhesive power thereof to the skin, or a method of making the adhesive layer gel by adding a liquid ingredient thereto so that the adhesive layer may have a soft touch. For the gel formation, a method has heretofore been employed, which comprises adding a crosslinking agent to an adhesive to increase the cohesive force thereof so that the adhesive layer may hold a liquid ingredient miscible therein.
Regarding the gel formation, however, when a basic drug is used in a percutaneous absorption-type pharmaceutical preparation, then it may react with a polyfunctional isocyanate or the like compound used as a crosslinking agent therein, and the crosslinking agent could not sufficiently exhibit its function. In such a case, it is known that a metal chelate or the like crosslinking agent may act predominantly, therefore exhibiting its effect.
Recently, however, it has been known that when a percutaneous absorption-type pharmaceutical preparation that comprises a gel of a combination of a basic drug and a metal chelate is applied to humans, then the crosslinked sites in the adhesive layer may be broken by lactic acid, a minor component of sweat perspiring through sweat glands, therefore causing cohesive failure in stripping the pharmaceutical preparation.
Regarding it, methods have been proposed for evading the problem; one comprising adding another component of polyalcohol so as to more conveniently exhibit the intrinsic effect of the metal chelate (Patent Reference 1: JP-A 2003-62058), and the other comprising planning a placebo layer that comprises a crosslinking agent not influenced by lactic acid for the adhesive layer to be in direct contact to the skin followed by superposing, as an upper layer thereon, an adhesive layer that contains a basic drug and is crosslinked with a metal chelate (Patent Reference 2: JP-A 2004-10525).
However, in the former method (Patent Reference 1), since the polyalcohol is a hydrophilic compound, it may uniformly dissolve in the adhesive layer that is in a hydrophobic environment, only in some degree (up to about 5%), and when its amount exceeds the limit, then there may occur a problem of its blooming from the adhesive layer. Accordingly, it has been found that, when a relatively large amount of a basic drug is incorporated in the adhesive layer, then a necessary amount of a polyalcohol could not be incorporated therein.
Regarding the latter method (Patent Reference 2), the cohesion failure on stripping, which is caused by the penetration and diffusion of lactic acid into the skin through the attached surface of the preparation, could be prevented, but in fact, since the sides of the percutaneous absorption-type pharmaceutical preparation are in contact with the skin in its application to the skin, it has been found that the occurrence of remarkable cohesion failure at the edges of the preparation owing to the penetration of lactic acid trough the sides thereof could not be evaded.